Persistence of cellular reservoirs is a major obstacle to eradication of HIV infection. The goal of this proposal is to determine whether adipose tissue contains an extensive but hitherto unsuspected HIV reservoir. Our hypothesis is based on the following: 1) T cells and macrophages are increased in dysfunctional adipose tissues (as in HIV patients); 2) Adipose tissue T cells are activated, producing cytokines that accelerate lipolysis, which enhances influx; 3) Memory T cells are increased, whereas Tregs are reduced, in dysfunctional adipose tissue; 4) Adipocytes produce factors (IL6 and VLA-1 ligands) to activate memory CD4+ T cells with increased HIV replication and viability; 5) HIV DNA (distinct env sequences) is in the stromal vascular compartment of adipose tissues in patients with undetectable plasma viral load; 6) Adipocytes may sequester lipophilic cART drugs and to HIV-infected cells. In the R21 phase the following Specific Aims are proposed: 1) Identify, in adipose tissue samples from treated HIV-infected persons with undetectable plasma viral load: a) integrated HIV DNA, HIV mRNA and replication-competent HIV in the stromal vascular compartment; b) function of immune cells; c) adipocyte factors that activate immune cells; 2) Determine, in adipose tissues compared with peripheral blood from SIV-infected rhesus macaques, SIV RNA, sequences of SIV DNA, and T cell phenotypes and responses; 3) Determine penetration of current drugs in adipose cells in vitro and in human adipose samples. In the R33 phase, we will define mechanisms underlying persistence of the adipose tissue reservoir and test targeted therapies to overcome this barrier, through the following Specific Aims: 1) Determine the timing of seeding of SIV after infection of rhesus macaques by measuring levels of SIV RNA, sequences and replication competence of SIV DNA, and T cell phenotypes and responses within adipose tissues, associated lymph nodes and peripheral blood; 2) Determine, in chronically SIV-infected rhesus macaques, whether current cART drugs accumulate in the adipocyte and stromal vascular compartments of adipose tissues, and eradicate SIV; 3) Determine whether novel drugs that bypass adipocyte sequestration or overcome adipocyte-induced viability of infected immune cells eradicate SIV in this reservoir. The clinical impact of an HIV reservoir in adipose tissue is considerable, accounting for as many as 1 - 5 x 108 HIV-infected immune cells. Our collaborative investigative team of specialists in HIV immunology, HIV-related adipose/lipid biology, SIV/macaque research and HIV pharmacology will investigate an innovative hypothesis highly responsive to the TaPHIR.